Connective tissue disease-associated ILD

Overview

•Lower zone ILD - most CTDs (RA, SSc, PM/DM, Sjögren's) → NSIP or UIP pattern

•Upper zone ILD - ankylosing spondylitis (apical fibrobullous disease); also TB, silicosis, coal workers' pneumoconiosis, sarcoidosis, HP

•Drug-induced ILD (amiodarone, methotrexate, nitrofurantoin, leflunomide) → lower zone fibrosis - mimics CTD-ILD

🎯

Ankylosing spondylitis is the only CTD causing upper-zone fibrosis. All other CTDs cause lower-zone predominant ILD. Amiodarone causes lower-zone fibrosis and is a classic exam trap in patients with both a CTD and a drug that causes ILD.

Investigations

🥇 First-line

•HRCT chest - identifies ILD pattern; PFTs - restrictive defect (reduced FVC, preserved FEV1/FVC, reduced TLC), reduced DLCO

•Autoantibody screen - ANA, RF, anti-CCP, anti-Scl-70, anti-Jo-1, anti-Ro/La to identify underlying CTD

🏆 Gold standard

•Surgical lung biopsy (VATS) - reserved for cases where HRCT pattern is uncertain

Management

🥇 First-line

•mycophenolate mofetil (MMF) - preferred for most CTD-ILD (especially SSc-ILD, PM/DM-ILD)

•Alternative first-line: azathioprine - if MMF not tolerated; prednisolone for induction in inflammatory patterns (NSIP, OP)

🥈 Second-line

•nintedanib - antifibrotic, NICE-approved for progressive pulmonary fibrosis (PPF) including CTD-ILD; pirfenidone - antifibrotic for PPF phenotype

•Refractory: rituximab - anti-CD20; used in refractory RA-ILD and myositis-associated ILD

⚠️

Always stop the offending drug before attributing ILD to the CTD itself. Methotrexate (used in RA) causes drug-induced pneumonitis that clinically mimics RA-ILD - stopping it is both diagnostic and therapeutic.

Prognosis

•NSIP > UIP in prognosis (more responsive to immunosuppression)

•SSc-ILD has the worst prognosis among CTDs; ILD is the leading cause of SSc mortality

•Poor prognostic markers: UIP pattern, FVC <70% predicted, DLCO <40% predicted, rapid PFT decline, pulmonary hypertension, male sex in RA-ILD

CTD-ILD patterns at a glance

Upper vs lower zone ILD causes

Feature	Upper zone	Lower zone
CTD	Ankylosing spondylitis	RA, SSc, PM/DM, Sjögren's, SLE
Occupational	Silicosis, coal workers' pneumoconiosis	Asbestosis
Infection	TB	-
Drug	-	Amiodarone, methotrexate, nitrofurantoin
Other	Sarcoidosis, HP	IPF (UIP pattern)

Histological patterns

•NSIP - most common in CTDs; temporally uniform, ground-glass opacity, lower zone, subpleural sparing; responds better to treatment, better prognosis

•UIP - honeycombing, traction bronchiectasis, subpleural basal predominance; worst prognosis; RA-ILD with UIP approaches IPF prognosis